The primary goal has been the elucidation of the structure of reactive metabolites which are responsible for the carcinogenic, cytotoxic, and mutagenic activity of benzo[a]pyrene and other polycyclic hydrocarbons. The approach taken consists of: i) synthesis of primary oxidative metabolites as well as selected secondary oxidative metabolites, ii) study of the metabolism of these hydrocarbons with liver microsomes, as well as with purified and reconstituted cytochrome P-450 systems with and without epoxide hydrolase, iii) tests for inherent mutagenicity of the synthetic metabolites toward bacterial and mammalian cells, iv) elucidation of the roles of the cytochrome P-450 system and epoxide hydrolase in potentiating or obliterating the mutagenicity of these metabolites, v) determination of the carcinogenic activity of these compounds, vi) determination of the rate of formation and nature of the products formed when reactive metabolites such as arene oxides and diol epoxides reacat with biopolymers and less complex model compounds, and vii) search for compounds capable of preventing the tumorigenic action of bay-region diol epoxides. A general theory of hydrocarbon-induced carcinogenesis, the bay-region theory, has been formulated and its predictions are being tested with synthetic potential metabolites of several hydrocarbons. Based on the presently available data, the bay-region theory has excellent predictive value. Comparative solvolytic studies of benzo-ring diol epoxides in which either the diol portion or the epoxide portion forms part of a bay-region have established that preferred conformation is a major factor in determining reaction rate. Tumorigenicity is not predictable based on solvolytic reactivity alone. Biological studies have shown that a bay-region 3,4-diol-1,2-epoxide of benz[c]acridine is an ultimate carcinogen. The bay-region (+)-(1R,2S,3S,4R) diol epoxide of benz[a]anthracene has been established as the most important ultimate carcinogen of this hydrocarbon. Several naturally occurring plant phenols have been shown to have potent antimutagenic activity toward bay-region diol epoxides. A new synthesis of optically active K-region arene oxides has been devised.